Article

The use of topical analgesics in the management of painful diabetic neuropathy Miranda Tawfik Citation: Tawfik M (2016) The use of topical analgesics in the management of painful diabetic neuropathy. Diabetic Foot Canada 4: 10–3

Article points 1. Painful diabetic neuropathy affects up to half of patients with diabetes. 2. Oral pharmacological therapy is the standard approach, but its use is limited due to side-effects and limited response rates. 3. This article reviews the rapidly expanding field of topical analgesia in the management of painful diabetic neuropathy.

Key words - Diabetic neuropathy - Pain management - Topical analgesia

Author Miranda Tawfik, Compounding Pharmacist and Owner of ORIGINS Pharmacy, Oakville Trafalgar Memorial Hospital and Total Health Compounding Pharmacy, Newmarket, Ontario

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Painful diabetic neuropathy (PDN) affects up to half of patients with diabetes and is a major cause of functional impairment and increased mortality. Its clinical manifestations include sensations such as burning, stabbing and tingling and/or loss of sensation, and it increases the risk for injuries and foot ulceration. Oral pharmacological therapy is the standard approach to management. It is effective in some patients, but its use is limited due to unfavourable side-effect profiles, limited response rates and drug interactions. Increasing evidence of the localized, nonsystemic treatment approach of topical analgesics aims to overcome these obstacles and provide valuable, efficacious and safe management of PDN. This article reviews the rapidly expanding field of topical analgesia in managing PDN.

O

ral pharmacological therapy is the traditional approach for the management of painful diabetic neuropathy (PDN). Current guidelines recommend starting with medications initially developed for the treatment of seizures and depression (Box 1; Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2013). Opioids, such as morphine and oxycodone, are usually considered when treatment failure occurs with first-line therapies, but are used with caution due to the risk of dependence and dose-related sideeffects. Despite its established place in therapy, the use of oral medications imposes obstacles to many patients with PDN, as management of their pain is frequently complicated by multiple co-morbidities and polypharmacy. Even so, evidence shows that only partial pain reduction is achieved in patients with PDN treated with oral pharmacotherapy (Krein et al, 2005). For these reasons, patients suffering from painful diabetic neuropathy are often ideal candidates for topical analgesics. Box 1 summarizes recommendations for screening and treatment of PDN. Patients with PDN often have multiple chronic conditions, organ dysfunction (renal, hepatic) and other risk factors (cardiac, gastro-intestinal) that

put them at risk of drug interactions and adverse events (Wild et al, 2004). Topical analgesics deliver medication directly to the site of pain, providing the same therapeutic benefit as their oral counterparts, with a rapid onset, minimal to no side-effects and without the risk of adverse events. For patients who are already on oral medications for PDN, topical agents may be used as an adjuvant or may completely replace their oral regimen for pain (Barton et al, 2011; Somberg et al, 2015). For the purposes of this discussion, it is important to distinguish between topical and transdermal application, as these terms should not be used interchangeably. Topical application aims to achieve a local effect, with very minimal systemic absorption and negligible side-effects. Transdermal application aims to achieve systemic absorption from local application, and the risks of side effects are increased, although possibly less so than if taken orally (Jorge et al, 2010). Recent literature suggests that peripheral neuropathic pain stems from multiple pathways (Sawynok, 2005). Oral medications typically address only one of these mechanisms, often leading to suboptimal efficacy. Pain is best managed by combination therapy, but combining various oral medications increases risks of adverse events from

Diabetic Foot Canada Volume 4 No 2 2016

The use of topical analgesics in the management of painful diabetic neuropathy

drug interactions and side effects, and reduces patient compliance. Combination of various analgesics into a single topical formulation provides multimodal pain control with significantly less risk of the adverse events and drug interactions typically associated with oral therapy. With the exception of local skin reactions – localized allergic reactions or skin irritation – topical pain relief is quite safe. However, it is not the most convenient option when large areas are affected. The advantages of topical analgesics, as compared to oral analgesics are highlighted in Box 2.

Topical analgesic agents used in the treatment of neuropathic pain Multiple therapeutic targets in the skin can be affected by topical analgesia, either alone or in combination with anti-inflammatory agents. Topical therapy, in addition to being safe and effective, typically has a more rapid onset of action and thereby may be considered an important treatment modality for the management of neuropathic pain. Table 1 summarizes the common doses of agents used in topical preparations. Non-steroidal anti-inflammatories (NSAIDs) Many clinical trials and reviews have proved the efficacy of topical NSAIDs (notably ibuprofen, diclofenac and ketoprofen) for various musculoskeletal and arthritic pain syndromes (Ahmed et al, 2015; Argoff, 2013). Recently, low-grade inflammation has been identified as a peripheral therapeutic target for PDN and justifies the usage of topical NSAIDs in this condition. NSAIDs work to inhibit the enzyme cyclo-oxygenase, which ultimately blocks the inflammatory cascade. Unlike oral NSAIDs, there have been no renal, cardiac or gastrointestinal adverse events from topical administration, likely due to low systemic absorption (Di Rienzo Businco et al, 2004; Nasri-Heir et al, 2013). Lidocaine Lidocaine is a targeted peripheral anaesthetic that works by binding to sodium channels on damaged nociceptors and reducing the firing of abnormal action potentials. The use of lidocaine 5% cream, either alone or combined with other topical analgesics, has demonstrated safety and efficacy in

Diabetic Foot Canada Volume 4 No 2 2016

Box 1. Summary of recommendations for painful diabetic neuropathy (Canadian Diabetes Association Clinical Practice Guidelines Expert Committee, 2013). 1. In people with type 2 diabetes, screening for peripheral neuropathy should begin at diagnosis of diabetes and occur annually thereafter. In people with type 1 diabetes, annual screening should commence after 5 years’ post pubertal duration of diabetes [Grade D, Consensus]. 2. Screening for peripheral neuropathy should be conducted by assessing loss of sensitivity to the 10-g monofilament or loss of sensitivity to vibration at the dorsum of the great toe [Grade A, Level 1]. 3. People with diabetes should be treated with intensified glycemic control to prevent the onset and progression of neuropathy [Grade A, Level 1A, for type 1 diabetes; Grade B, Level 2, for type 2 diabetes]. 4. The following agents may be used alone or in combination for relief of painful peripheral neuropathy: a. Anticonvulsants (pregabalin [Grade A, Level 1], gabapentin, valproate [Grade B, Level 2]. b. Antidepressants (amitriptyline, duloxetine, venlafaxine) [Grade B, Level 2]. c. Opioid analgesics (tapentadol extended-release, oxycodone extended-release, tramadol) [Grade B, Level 2]. d. Topical nitrate spray [Grade B, Level 2].

the management of painful diabetic neuropathy (Madsen et al, 2013). Recently, a non-inferiority study comparing lidocaine 5% plaster to oral pregabalin (Lyrica) in patients with post-herpetic neuralgia and PDN demonstrated that lidocaine 5% provided similar relief with lower risk of adverse events as compared to pregabalin (Baron et al, 2009). Gabapentin Gabapentin is an anti-epileptic medication used to treat neuropathic pain. However, its efficacy Box 2. Advantages of topical analgesics. • Increased concentration of drug at site of pain. • Decreased potential for drug interactions. • Reduction or elimination of systemic side-effects (eg, sedation, cognitive impairment). • No

adverse

effects

on

internal

organs

(gastrointestinal, cardiac, renal, or hepatic effect). • Fast onset of pain relief. • Localized, targeted relief of pain and inflammation. • Dose reductions of oral pharmacologic agents. • Reduced addictive/abuse potential. • Increased adherence/patient compliance. • Easy and safe to administer.

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The use of topical analgesics in the management of painful diabetic neuropathy

Table 1. Topical analgesics and common strengths. Drug class

Ingredient

Dose range

NSAIDs

Diclofenac

5–10%

Ibuprofen

5–10%

Ketoprofen

10–20%

Lidocaine

2–5%

Ketamine

2–10%

Amitriptyline

2–4%

Doxepin

3–5%

Anti-epileptics

Gabapentin

5–10%

Antihypertensives

Clonidine

0.1–0.2%

Muscle relaxants

Baclofen

2–5%

Calcium channel blockers

Nifedipine

2–16%

Counter-irritant

Capsaicin

0.025–8%

Vasodilators

Isosorbide dinitrate

30mg

Anaesthetics

Tri-cyclic antidepressants

is limited by its dose-related side-effects (Hiom et al, 2015). Although the precise mechanism is unknown, topical administration appears to produce local antinociception. A recent study by Hiom et al (2015) described the use of topical gabapentin 6% in the treatment of various neuropathic conditions, including painful diabetic polyneuropathy. It was noted that 87% of the patients reported benefit from topical gabapentin, with results achieved within 1 hour of application. Tricyclic antidepressants: amitriptyline and doxepin Amitriptyline is a tricyclic antidepressant with effective analgesic properties (Saarto and Wiffen, 2007). Side-effects, including dry mouth, constipation, sweating, dizziness, sedation and cardiovascular effects, limit its use (Max et al, 1987; 1992). Its topical use has been widely studied, often in combination with other agents such as topical NSAIDs, lidocaine and ketamine (Gewandter et al, 2014; Barton et al, 2011). Studies reflect doserelated efficacy as well as relief, sometimes within 20 minutes. Doxepin 5% is commercially available in the US and has been studied and found effective for treatment of PDN. Doses as low as 3% have been shown to be efficacious in the treatment of PDN (McCleane, 2000).

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Clonidine Clonidine is an α-2 receptor agonist used to treat hypertension and known to exhibit analgesic properties centrally (Campbell et al, 2012). Topical application of clonidine was found to significantly reduce PDN when 0.1% was applied three times daily, with no significant changes to blood pressure (Byas-Smith et al, 1995). Baclofen Baclofen is a GABA-b receptor agonist that works as an anti-spasmodic and muscle relaxant centrally and exhibits analgesia peripherally. Research shows promising results when used alone for various neuropathic cases as well as in combination with other topical agents (Fromm et al, 1984). The topical administration of amitriptyline 40mg, baclofen 10mg and ketamine 20mg for patients with chemotherapy-induced neuropathies resulted in improvement of pain and was well tolerated (Barton et al, 2011). Ketamine Ketamine, a potent analgesic and anaesthetic, works by noncompetitively blocking the excitatory NMDA glutamate receptor. It has been shown to reduce hyperalgesia and allodynia without causing any systemic adverse reactions, and thus is useful in the management of PDN (Hocking and Cousins, 2003). Concentrations as high as 10% have shown negligible serum levels and its use has been described in a variety of applications for pain management, including post-surgical neuropathic pain, complex regional pain syndrome and postherpetic neuralgia (Lynch et al, 2003). In another study, a combination of ketamine with amitriptyline and lidocaine significantly reduced pain intensity, sharpness, burning, sensitivity, and itchiness of neuropathic pain due to radiation-induced neuropathy (Uzaraga et al, 2012). Nifedipine Nifedipine, a calcium channel blocker used orally to treat hypertension, also causes peripheral vasodilation and aids in tissue perfusion. In PDN, it is thought to improve healing and reduce pain by greatly improving tissue perfusion, improving healing and nerve conduction velocity (Goldenberg, 2013).

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The use of topical analgesics in the management of painful diabetic neuropathy

Capsaicin Topical capsaicin, a counter-irritant derived from chili peppers, is a commercially available topical therapeutic agent that is available without a prescription in concentrations of 0.025%, 0.075%, and most recently 8%. However, due to its counterirritant properties, initial pain upon application considerably limits its use and it has fallen out of favour despite its ready availability. A doubleblind, randomized clinical trial compared topical amitriptyline to capsaicin 0.075% in the treatment of PDN and found amitriptyline demonstrated similar efficacy with fewer side-effects (Kiani et al, 2015). Topical nitrate spray Isosorbide dinitrate spray is recommended in the treatment of PDN and seems to improve pain and burning sensations by peripheral vasodilation. Patients may experience transient headaches as a side-effect (Agrawal et al, 2007; Yuen et al, 2002).

Conclusion PDN is a common complication of diabetes that can result in significant limitations to patients’ ability to function and overall quality of life. It is often difficult to treat and can be a source of frustration to both patients and their caregivers. Emerging evidence on the safety and efficacy of topical agents for the relief of neuropathic pain may help to address an unmet need. A growing body of literature has validated both the efficacy and safety of topical treatment for the management of PDN. Topical analgesia is a very promising avenue for clinical improvement in the management of patients with PDN and can be successfully used to supplement or replace conventional systemic analgesic therapy. n Agrawal RP, Choudhary R, Sharma P, et al (2007) Glyceryltrinitrate spray in the management of painful diabetic neuropathy. Diabetes Res Clin Pract 77(2): 161–7 Ahmed SU, Zhang Y, Chen L et al (2015) Effect of 1.5% topical diclofenac on clinical neuropathic pain. Anesthesiology 123(1): 191–8 Argoff CE (2013) Topical analgesics in the management of acute and chronic pain. Mayo Clin Proc 88(2): 195–205 Baron R, Mayoral V, Leijon G, et al (2009) 5% lidocaine medicated plaster versus pregabalin in post-herpetic neuralgia and diabetic polyneuropathy. Curr Med Res Opin 25(7): 1663–76 Barton DL, Wos EJ, Qin R et al (2011) A double-blind, placebocontrolled trial of a topical treatment for chemotherapyinduced peripheral neuropathy. Support Care Cancer 19(6): 833–41 Byas-Smith MG, Max MB, Muir J, Kingman A (1995) Transdermal clonidine compared to placebo in painful

Diabetic Foot Canada Volume 4 No 2 2016

diabetic neuropathy using a two-stage ‘enriched enrollment’ design. Pain 60(3): 267–74 Campbell CM, Kipnes MS, Stouch BC et al (2012) Randomized control trial of topical clonidine for treatment of painful diabetic neuropathy. Pain 153(9): 1815–23 Canadian Diabetes Association Clinical Practice Guidelines Expert Committee (2013) Canadian Diabetes Association 2013 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. Can J Diabetes 37(Suppl 1): S1–212 Di Rienzo Businco L, Di Rienzo Businco A, D’Emilia M et al (2004) Topical versus systemic diclofenac in the treatment of temporo-mandibular joint dysfunction symptoms. Acta Otorhinolaryngol (Ital) 24(5): 279–83 Fromm GH, Terrence CF, Chattha AS (1984) Baclofen in the treatment of trigeminal neuralgia. Ann Neurol 15(3): 240–4 Gewandter JS, Mohile SG, Heckler CE, et al (2014) A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy. Support Care Cancer 22(7): 1807–14 Goldenberg LM (2013) The care of the diabetic foot. Available at: http://bit.ly/2enXV0e (accessed 21.10.16) Hiom S, Patel GK, Newcombe RG et al (2015) Severe postherpetic neuralgia and other neuropathic pain syndromes alleviated by topical gabapentin. Br J Dermatol 173(1): 300–2 Hocking G, Cousins MJ (2003) Ketamine in chronic pain management: An evidence-based review. Anesth Analg 97(6): 1730–9 Jorge LL, Feres CC, Teles VE (2010) Topical preparations for pain relief: efficacy and patient adherence. J Pain Res 4: 11–24 Kiani J, Nasrollahi SA, Esna-Ashari F et al (2015) Amitriptyline 2% cream vs. capsaicin 0.75% cream in the treatment of painful diabetic neuropathy. Iran J Pharm Res 14(4): 1263–8 Krein SL, Heisler M, Piette JD et al (2005) The effect of chronic pain on diabetes patients’ self-management. Diabetes Care 28(1): 65–70 Lynch ME, Clark AJ, Sawynok J (2003) A pilot study examining topical amitriptyline, ketamine, and a combination of both in the treatment of neuropathic pain. Clin J Pain 19(5): 323–8 Madsen CS, Johnsen B, Fuglsang-Frederiksen A et al (2013) Differential effects of a 5% lidocaine medicated patch in peripheral nerve injury. Muscle Nerve 48(2): 265–71 Max MB, Culnane M, Schafer SC et al (1987) Amitriptyline relieves diabetic neuropathy pain in patients with normal or depressed mood. Neurology 37(4): 589–96 Max MB, Lynch SA, Muir J et al (1992) Effects of desipramine, amitriptyline, and fluoxetine on pain in diabetic neuropathy. N Engl J Med 326: 1250–6 McCleane GJ (2000) Topical doxepin hydrochloride reduces neuropathic pain: a randomised, double-blind, placebo controlled study. The Pain Clinic 2: 47–50 Nasri-Heir C, Khan J, Heir GM (2013) Topical medications as treatment of neuropathic orofacial pain. Dent Clin North Am 57(3): 541–53 Saarto T, Wiffen PJ (2007) Antidepressants for neuropathic pain. Cochrane Database Syst Rev (4):CD005454 Sawynok J (2005) Topical analgesics in neuropathic pain. Curr Pharm Des 11(23): 2995–3004 Somberg JC, Molnar J (2015) Retrospective study on the analgesic activity of a topical (TT-CTAC) cream in patients with diabetic neuropathy and other chronic pain conditions. Am J Ther 22(3): 214–21 Uzaraga I, Gerbis B, Holwerda E et al (2012) Topical amitriptyline, ketamine, and lidocaine in neuropathic pain caused by radiation skin reaction. Support Care Cancer 20(7): 1515–24 Wild S, Roglic G, Green A et al (2004) Global prevalence of diabetes: Estimates for the year 2000 and projections for 2030. Diabetes Care 27(5):1047–53 Yuen KC, Baker NR, Rayman G (2002) Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray. Diabetes Care 25(10): 1699–703

“A growing body of literature has validated both the efficacy and safety of topical treatment for the management of PDN.”

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